In the US, alcoholism is a serious disorder that will affect 14% of the population at some point in their lives. 100,000 US citizens will die of alcoholism each year from direct and indirect causes at a cost of $166 billion per year. In addition to contributing to traumatic death and injury (e.g., through car crashes), alcoholism is associated with chronic liver disease, cancers, cardiovascular disease, acute alcohol poisoning (i.e., alcohol toxicity), and fetal alcohol syndrome. Alcoholism is a chronic relapsing disorder characterized by multiple stages and multiple sources of motivation for excessive intake of the drug (i.e., the addiction cycle). The acute effects of ethanol are both reinforcing and rewarding in animal models such as operant self-administration and conditioned place preference. For medications development, several animal models including excessive drinking during dependence have been developed. Strengths of this model are that it represents a critical aspect of construct validity and is reliable. For example, recent work points to this animal model as a sensitive measure of opioid drug efficacy. Naltrexone, a mu-opioid receptor antagonist, is one of few drugs approved by the US FDA for treating alcoholism. However, naltrexone use is associated with dose-dependent hepatotoxic side effects that complicates its use and confounds treatment of alcoholic patients with liver disease. Additional shortcomings include less than desirable duration of action and relatively low bioavailability, gradual diminishing of beneficial effects over time, and possibly, a relatively low affinity for delta and kappa receptors thought to contribute to diminishing the reinforcing effects of drinking alcohol. Nalmefene, a compound closely related to naltrexone, offers promise but has similar drawbacks. Therefore, an important goal of alcoholism therapeutics research remains to identify new and safer compounds that are more effective at suppressing alcohol consumption with reduced toxicity. We have generated novel compounds with enhanced in vivo potency and superior pharmaceutical properties, including greater metabolic stability, that are expected to increase duration of action and decrease hepatotoxicity. The lead compound represents a new class of therapeutic for use in treating alcoholism, and has been selected for advanced preclinical drug development. The Aims of Phase I work are: 1) Re-synthesize the lead compound 2) Evaluate the lead compound in an alcohol-dependent animal model informative in studies of alcohol consumption and 3) Summarize the data prior to advanced preclinical IND-enabling studies. The Aims of Phase II include: 1) Refine the lead compound in a second alcohol-dependent animal model of excess drinking, 2) Fully characterize the biopharmaceutical properties of the lead compound, 3) Do IND enabling studies of the compound, and 4) Validate the medications development of the compound for clinical trials of human alcohol cessation. Completion of the proposed Fast Track Aims will show the efficacy of the lead compound in anti-alcoholism effects and afford a novel pharmacological agent for eventual pharmacotherapy in human clinical trials of alcoholism. PUBLIC HEALTH RELEVANCE: The need for potent, orally active medications to address diseases of alcohol and drug abuse is immense. Development of the lead compound affording a long-acting anti-alcoholism agent that possesses an improved side effect profile compared to drugs currently on the market will provide a therapeutic that is currently not available. The potential commercial application of the work is that the research could lead to a "blockbuster" drug product.